Pathological elevation of peripheral prolactin (PRL) levels, hyperprolactinemia (hyperPRL) in men is associated with disturbances of reproductive functions including hypogonadism, loss of libido and impotence. Mechanisms responsible for the effects of hyperPRL remain to be elucidated. We will utilize animals with experimentally induced hyperPRL to identify these mechanisms. Hyperprolactinemia will be induced by transplantation of several pituitaries from adult females under the kidney capsule of recipient males or by chronic treatment with estrogen. Hyperprolactinemic and control animals will be compared with respect to levels and turnover rates of hypothalamic neurotransmitter: norepinephrine (NE), dopamine (DA) and serotonin (5HT), regulation of luteinizing hormone- releasing hormone (LHRH) release, secretion of LH and FSH by the pituitary and sexual behavior under standardized testing conditions. We will also examine the effects of hyperPRL on the control of pituitary hormone release by opiatergic and gamma aminobutyric acid (GABA)-ergic neurons and on the responsiveness of the hypothalamus-pituitary system to the negative feedback control by testicular steroids. Several specific hypotheses on the mechanisms of action of hyperPRL are proposed and will be tested during the next five years. Previously demonstrated differences in the effects of hyperPRL in rats, mice and hamsters will be exploited to identify cause-effect relationships between the hyperPRL-induced changes in the activity of NE, DA and 5HT neurons in the hypothalamus and alterations in pituitary hormone release and reproductive behavior. In addition, we will study mechanisms responsible for disruption of the normal hypothalamic control of PRL release associated with induction of persistent hyperplasia of PRL- producing cells by chronic estrogen treatment. Abnormal pituitary function during and after treatment of susceptible animals with estrogen shares many characteristics with the behavior of PRL-secreting tumors, prolactinomas, in the human. Studies proposed in this application will involve measurements of NE, DA, 5HT, their precursors and metabolites, incubation of hypothalamic and anterior pituitary tissue for examination of the control of LHRH and LH release in vitro, administration of blockers of neurotransmitter synthesis, and placement of lesions in areas involved in mediating the effects of hyperPRL on reproductive functions. It is anticipated that the proposed studies will answer a number of questions concerning influence of abnormally elevated peripheral PRL levels on male endocrine functions and reproductive behavior.